Microbiome-mediated modulation of immune memory to P. yoelii affects the resistance to secondary cerebral malaria challenge 2521

Abstract

Malaria is caused by protozoan parasites in the genus Plasmodium. Over time individuals slowly develop clinical immunity to malaria, but this process occurs at variable rates, and the mechanism of protection is not fully understood. We have recently demonstrated that gut microbiota composition dramatically impacts the quality of the humoral immune response to P. yoelii and subsequent protection against lethal P. berghei ANKA-induced experimental cerebral malaria (ECM) in C57BL/6N mice.? Here, we utilize this model to investigate how the gut microbiota modulates immunological memory, hypothesizing that the gut microbiome impacts the formation and functionality of immune memory. Despite differences in protection against ECM, P. yoelii-resistant and -susceptible mice accumulate similar numbers of memory B cells (MBCs) and memory T cells. Following challenge with P. berghei ANKA, P. yoelii-resistant mice generated more rapid germinal center reactions, however, P. yoelii-resistant and susceptible mice had similar titers of P. yoelii and P. berghei-specific antibodies. In contrast, P. yoelii-resistant mice had an increased number of regulatory T cells in response to secondary challenge with P. berghei ANKA, which may dampen the immune-mediated breakdown of the blood-brain barrier and susceptibility to P. berghei-induced ECM. These findings demonstrate the ability of the gut microbiome to shape immune memory and the potential to enhance resistance to severe malaria outcomes.? Funding Sources Supported by T32 AI060519 Immunology and Infectious Diseases Training Program; Funds from Indiana University School of Medicine; Support provided by the Herman B. Wells Center was in part from the Riley Children’s Foundation; The project described was supported by the Indiana University Health-Indiana University School of Medicine Strategic Research Initiative Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)